Introduction: Our group is investigating the neural substrates of emotion, mood, and temperament in healthy volunteers and patients with mood disorders. We are particularly interested in exploring the cerebral concomitants of varying affective experiences and how disruptions of such processes in mood disorders relate to clinical factors such as symptom profile, course of illness, and responses to somatic therapies. We hypothesize that a subcortical (anterior paralimbic) processor contributes to mediation of primitive, rapid response, action-oriented affective experiences known as emotions, and that an overlying (prefrontal) neocortical processor contributes to mediation of more refined, more sustained, cognition-oriented affective experiences known as moods. Interactions between the subcortical emotional and neocortical mood processors may contribute to mediation of integrative, enduring modulation of affective tone known as temperament. Methods: We are using positron emission tomography (PET), and magnetic resonance spectroscopy (MRS) to explore cerebral glucose metabolism and biochemistry at rest and during affective (transient self-induced sadness) activation. We are also using structural magnetic resonance imaging (MRI) to assess cerebral volumes and subcortical hyperintensities. Results/Conclusions: We are particularly interested in detecting baseline functional cerebral markers of subsequent responses to psychotropic agents. If successful, such techniques could allow more effective targeting of therapies in patients with refractory mood disorders.